Abstract: Gliomas are the most commonly diagnosed primary brain tumors, accounting for approximately 45-50% of all primary brain tumors. Glioblastoma multiforme (GBM) is the most aggressive of the primary brain cancers and despite advancements in surgery, radiation and chemotherapy, remains incurable. Further, human cytomegalovirus (hCMV) has been implicated in the development and progression of human glioblastomas through unknown mechanisms. The presence and role of hCMV infection in glioblastomas and GBM has remained a controversial topic over the last decade. Nonetheless, several groups have demonstrated the presence of CMV nucleic acids and proteins in primary and recurrent GBM specimens using immunohistochemistry (IHC), RNA and DNA in situ hybridization (ISH), qualitative and quantitative real-time PCR coupled with viral DNA sequencing, and western blot (WB) analysis. Subsequent research, including our preliminary studies, has also demonstrated that several hCMV gene products that have oncomodulatory properties are expressed in GBM and may be impacting tumor pathogenesis in vivo by modulating GBM proliferation, apoptosis, angiogenesis, invasion and immune evasion. Because HCMV is a ubiquitous human virus that infects 50-90% of adults in the US, investigation of its potential oncomodulatory role in glioblastomas, particularly the aggressive GBM, is highly relevant. We hypothesize that persistent HCMV infections lead to a dysregulation of the cellular epigenetic environment that results in the overexpression of EZH2 and activation of the STAT3 pathway to enhance tumor pathogenesis in glioblastoma. To test this hypothesis, we will: 1) Determine whether HCMV persistence enhances tumor pathogenesis in glioblastoma cells through the dysregulation of epigenetic pathways involved in cell cycle control and differentiation. 2) Establish the role of HCMV persistence in tumor progression and glioblastoma drug resistance in intracranial xenografts. 3) Determine whether overexpression of EZH2 correlates with incidence of HCMV infection in glioblastoma biopsies. The long-term goal is to identify novel pathways regulated through HCMV persistent infection that could lead to glioblastoma tumor progression and CNS invasion. The results of this research are expected to provide the framework for future studies testing therapeutic interventions, which maintain the normal epigenetic state of a cell and decrease the risk of CMV-associated tumor progression.